Melanoma incidence is rising faster than any other cancer. Surgery can be curative at early stages, but metastatic melanoma is typically fatal. Responses to new targeted and immunotherapies can be remarkable in select cases, but low response rates, acquired resistance, and severe adverse side effects (particularly for combination immunotherapies) limit long-term quality of life for these patients. Thus, despite what is rightly seen as a revolution in advanced-stage melanoma treatment, the overall response rate to all therapies remains dismally near 50% and the 5-year survival is <25%. Despite these shortcomings, there is a clear and growing market for advanced melanoma drugs (2016 global revenues $4Bln; expected CAGR 15%). Further, receptor- targeted radionuclide therapies are emerging as valuable products in oncology. Two recent acquisitions by large pharma: Algeta by Bayer in 2014 ($2.9Bln); and Advanced Accelerator Applications by Novartis in 2017 ($3.9Bln) highlight this value. Viewpoint identified an initial indication for its MCR1-targeted radionuclide therapy of progressive stage 4 metastatic melanoma (potential global annual revenues $600Mln). However, emerging evidence suggests a synergistic role for ionizing radiation (IR) combined with immunotherapy to promote immunogenic cancer cell death. Current external beam IR relies on an abscopal effect because IR delivered in this way can only be directed to individual lesions. Because of known intertumoral heterogeneity of melanoma, the advantage of systemic MC1R-RT is precise deposition of radiation in all metastatic lesions, which has the potential to improve the repertoire of neoantigens presented to the immune system. Thus, there is a critical need to determine the feasibility of safely combining immunotherapies with MC1R-RT for metastatic melanoma. Proof-of-concept study results support the hypothesis that this combination can expand our indication to a front-line therapy. The State of Iowa will match $50k upon award for this project. BUSINESS RATIONALE: Success in combining MC1R-RT with immunotherapy to safely improve rates of overall and complete response for malignant melanoma potentially expands our indication to a frontline combination therapy for all metastatic melanoma patients, which would significantly increase our valuation. AIM 1: Determine the feasibility of safely combining MC1R-RT (90Y) with immunotherapies to improve tumor response rates and survival in two immune-competent mouse melanoma models. IMPACT and SIGNIFICANCE: Successful completion of this Aim will establish the feasibility of safely combining Viewpoint?s proprietary MCR1-targeted radionuclide therapy with immunotherapies for malignant melanoma. This work if successful will also establish a robust biochemical and immunological rationale for further development of MC1R-RT in clinical trials designed to overcome low response rates, acquired resistance, and serious side effects that limit current malignant melanoma therapies.